Under normal circumstances, the body recognizes and treats its own tissue components as “self”, without immune response, which is self-tolerance. Self-tolerance occurs because the lymphocyte clones that recognize its own tissues are destroyed or forbidden during the embryonic development, as stated in Burnet's forbidden clone theory. However, in some cases, self-tolerance is compromised and the forbidden clones are re-activated, so that the body's immune system initiates immune response against its own tissue components, which leads to autoimmune diseases. The key is that the organism produces autoantibodies or sensitized T lymphocytes that react with its own tissue components and lead to the damage of the tissue and cells. The mechanism on the production of autoantibodies and sensitized T cells is very complicated. The following factors may play a role, according to research findings.
First, the Emergence of Autoantigen
1. Release of Sequestered Antigens
Sequestered antigens refer to tissue components, such as sperm, intraocular soluble components, brain tissue, etc, that normally do not contact with immune cells. However, their corresponding immune cell clones exist and are immune-responsive. When the isolation barrier is damaged due to surgery, trauma, infection and other reasons, the sequestered antigens are released into the bloodstream or lymph. The immune system mistake them as “foreign agents”, trigger the autoimmune response, and result in the autoimmune disease.
2. Changes of Tissue Components
The antigenicity of tissue components may change due to physical factors (such as cold, heat, ionizing radiation), chemical factors (such as drugs), or biological factors (such as bacteria, viruses, etc.). The changed tissue components can stimulate an autoimmune response, and result in autoimmune diseases.
3. Cross-Reactivity
Some bacteria and viruses have similar epitopes as those on normal human tissue cells. The antibodies and sensitized lymphocytes produced against the foreign agents may cross react with the human epitopes, which finally result in autoimmune diseases.
Second, Abnormal Immune Response
1. Bypass Activation of Lymphocyte
Under normal circumstances, both autoantigen-specific T and B lymphocyte clones exist in the body. B lymphocytes can respond to autoantigens while the Th cells are irresponsive. With inactivated Th cells, B cells can't produce autoantibodies. Some foreign antigens have similar or identical determinants as those recognizable by B cells. Due to the difference of the carrier determinants recognized by various T cells, the Th cells that recognize autoantigens remain silent while those that recognize foreign agents are activated and in turn activate B cells to produce autoantibodies. Through this Th Bypass Activation, autoimmune response is initiated.
2. Bypass Activation of Polyclonal Stimulant
Some polyclonal stimulants, such as epstein-barr virus and super-antigens, are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the β-subunit of T-cell receptors in a non-specific fashion. Through this bypass activation, autoantibodies are produced and lead to the autoimmune response.
3. Abnormal Expression of Auxiliary Stimulating Factor
In the immune response, immune cell activation needs both the recognition by the immune active cells of the antigen peptide complex on the surface of the antigen presenting cells, and the interactions of auxiliary stimulating factors between the two cells. If the expression of the auxiliary stimulating factor on the surface of the antigen presenting cell is abnormal, this may activate the immune response of T cell and cause autoimmune diseases.
In addition, the imbalance of the functions of Th1 and Th2 cells are also related to the initiation of autoimmune diseases.
Third, Abnormal Expression of Fas/FasL
The abnormal expression of Fas/FasL is related to the genesis of autoimmune diseases. Fas belongs to the family of TNFR/NGFR (or CD95). It is present on the surface of a variety of cells including lymphocytes. Its ligand, FasL (Fas ligand), is usually expressed on the cellular membrane of the activated T cells such as CTL and NK cells. It can also be secreted into the extracellular space. Both free and membrane-bound FasL, when bind to membrane Fas, induce cell apoptosis. In the patients with Fas/FasL genetic defects, due to impaired apoptosis mechanism, the T and B lymphocyte clone proliferation is out of control, thus susceptible to various autoimmune diseases.
Fourth, Genetic Factors
Human autoimmune diseases often have family genetic predisposition. Research indicates that prevalence of many autoimmune diseases is correlated with detectability of certain HLA genotype. The correlation is mostly related to HLA-B or DR antigens.
For the development of allergy IVD, the positive control serum is an important tool, but the availability of positive sera for many autoantigens is very limited, if any. Approaches such as artificial sera have been attempted. For example, the patent CN103018436A published on Apr. 3, 2013, disclosed a method for preparing Infectious Bronchitis positive serum in rabbits. The whole blood from the immunized rabbit was centrifuged and filtered, and resulted in the positive serum. The crude preparation may result in low titers, which makes the artificial sera less valuable in the assay development.